Anxiety is a natural and normal response to situations that are stressful or fearful (1). Most people will experience some form of anxiety in reaction to stressful situations. Anxiety symptoms are usually transit and do not impair function (1). But when function is impaired, this is considered to be an anxiety disorder (1). There are different specific anxiety mood disorders, but in general the onset of SAD (social anxiety disorder) and GAD (generalized anxiety disorder) symptoms will precede major depressive disorder (1). But there is an equal chance of having PD (panic disorder) before, during, or after MDD (1).

The Epidemiological Catchment Area (ECA) study, which had a large influence in establishing the prevalence of psychiatric illnesses in the United States, suggests that the presence of two or more disorders is common in patients with psychiatric illnesses and is likely more common than a single diagnosis (1,2). The National Comorbidity Survey Replication (NCS-R) suggests that there is a strong association between lifetime risks for panic disorder and major depression (1,2). The rates of comorbidity with anxiety and depression will increase over time (1,2). Anxiety disorders could evolve into uncomplicated depression or can become the comorbid state with symptoms suggesting both depression and anxiety (3). Depression may sometimes progress to the comorbid state and less frequently will lead to an uncomplicated anxiety disorder (3). When comparing the uncomplicated panic or depression conditions, the comorbid condition has greater symptom severity and persistence (3). There is an also higher risk of suicides and greater functional impairment (3). It is suggested that there may be a general vulnerability factor for psychiatric functions that may be due to a personality tract that contributes to high anxiety and poor coping skills (3). There are not that many studies that are studied the biological factors and pathophysiological processes that are related to the anxious depressive comorbid state (3). There may be a significant contribution from genetic factors that lead to the development of major depression and generalized anxiety disorder (3). There is a significant ACTH response and a similar response for cortisol in response to a social stress test performed in comorbid individuals but not seen in those who had pure major depression or pure panic social anxiety (3). This suggests that there may be an abnormality present in the hypothalamus pituitary adrenal axis function that is associated with the comorbid state (3).

With regards to anxiety disorders, genetic and psychosocial factors play a role in the initiation and expression of anxiety disorders (1,2). Genetics may create a vulnerable phenotype for an anxiety disorder and the stressors that are present in one’s life may precipitate and continue the expression of the anxiety disorder (1,2). The thalamus and amygdale are important in generating a normal fear response and are a central role in nearly all anxiety disorders (1,2). The thalamus is the first region that processes the regional data to organize sensory data from the environment (1,2). This info is passed from the thalamus to the higher cortical centers for finer processing and to the amygdale which will assess the highly charged emotional information (1,2). It provides the importance emotionally to the information, which will help the organism to act quickly on vital events (1,2). Then the cortex will analysis in further detail which will send updates to the amygdale which enables a decision on a course of action (1,2). This is a disorder when the activity of the fear response network leads to maladaptive behavior or distress (1,2). Direct and indirect connections to the RAS, help regulate vigilance, fear and arousal (1,2). The modulation of these connections will rely on neurotransmitters such as serotonin, and NE. Increase in activity of the locus ceruleus in which NE producing cells reside will increase arousal, anxiety and panic (1,2). Drugs that decrease activity of this area will improve anxiety symptoms (1,2). The raphe nuclei are the home of the cell bodies that produce serotonin. Serotonin is important for regulation of the activity of the cells in LC (1,2). Overtime, an inhibition of the firing of noradrenergic cells will occur (1,2).


In order to diagnose the comorbid situation, it depends on an acute diagnosis of the individual disorders (1). This is based on the DSM-IV categorical diagnostic approach (1). In order to identify the presence of the anxious depressive comorbid state, individual diagnosis of a depressive disorder and anxiety must be present (1). KC has no diagnosis for anxiety. However, anxiety is a presenting feature of several major psychiatric illnesses (1). Symptoms of anxiety are very common in patients that have mood disorders, schizophrenia, delirium, dementia, and substance abuse disorders (1). A majority of the psychiatric patients will have two or more concurrent psychiatric disorders present in their lifetime (1). Comorbid mood disorders, especially depression should be treated as the primary condition (1). Physical examinations should be done to exclude any endocrine or cardiovascular disorders (1). It should also be done to rule out substance abuse (1). Common medical illnesses that are associated with anxiety symptoms include angina, congestive heart failure, Cushing’s disease, Parkinson’s disease, asthma and anemias. Drugs that are associated with anxiety symptoms include felodipine, quinolones, carbamazepine, stimulants such as amphetamines, and levothyroxine (1). Diagnosis is based on symptom expression and a history of questions that pertain to the description of the symptoms (1). The goals of treatment would be to diagnose and treat all of the possible comorbid psychiatric conditions that are present in patients with anxiety disorders (1,2). Additional goals of therapy would be to eliminate or decrease symptomatic anxiety, eliminate or decrease anxiety-based disability and prevent recurrence (1,2).

There are many different classifications for anxiety and GAD seems to be the best fit for KC. This form of anxiety is due to excessive and uncontrollable worry related to everyday-life concerns which includes the safety of family members, job and financial security and health (2). Patients that do have GAD frequently have depressed mood and other anxiety symptoms (2). The onset is in early adulthood on a typical basis and it emerges and dissipates more slowly than PD (2). Symptoms include excessive worrying about multiple events or activities during more days than not for at least 6 months (2). It is associated with restlessness, easily fatigued, poor concentration, irritability, muscle tension, and insomnia or unsatisfying sleep (2).


CBT is the most effective treatment that is psychosocial in nature, but will take 20 or more sessions to be effective (3). Management with psychotherapy can be successful. Treatment plan should be individualized based on the severity of the patient’s symptoms, preference, medical status and any other comorbid conditions (3). Other nonpharmacologic include reducing caffeine, alocohol intake (3). If the patient is taking short acting benzodiazepines, the as needed use should be reduced as much as possible (3). The goal is for not to use this drug for longer than 4 days (3). Stress reduction, which can include time management and relaxation training may be helpful initially (1,3). Stimulating agents such as decongestants and diet pills should be avoided as well (1,3). CBT is crucial as it will help patients recognize and alter patterns of dysfunctional behavior or distorted thinking (1,3). Trials suggest that treatment gains with CBT can last for a period of a year (1,3). Currently, it is unknown if CBT and medication is more effective than either treatment or CBT alone (1,3).

Pharmacologic therapy includes antidepressants, benzodiazepines, hydroxyzyine, pregabalin and buspirone (1,4). These agents have been shown in controlled clinical trials that support their use in treating GAD (4). However, the antidepressant agents have replaced BZD as the drugs of choice for chronic cases of GAD because of a better side effect profile, no risk for any dependency and furthermore efficacy in comorbid conditions such as depression, panic and SAD (1). BZDs, however are the most effective treatment for short term management of anxiety (1). It is used when fast relief of symptoms are required (1). These are also recommended intermittently or adjunctively during GAD exacerbations or for sleep disturbance during antidepressant therapy initiation (1). Patients that have GAD should be treated to achieve a remission of symptoms (1). The guidelines recommend continuing treatment for an additional 3 to 10 months (1).


These agents will help reduce the psychic symptoms of anxiety, such as worrying and apprehension (3,4). There is a modest effect on the autonomic symptoms that include tremor, rapid heart rate and sweating (3,4). All of the antidepressants evaluated have a similar degree of anxiety reduction (3,4). The onset of effect is delayed for a 2 to 4 week period (3,4). SSRIs and venlafaxine are preferred over TCAs due to better safety and tolerability (3,4). The antidepressants help modulate the synaptic 5-HT, Ne, and or DA reuptake, which modifies the expression of genes and proteins that are important in stress response (3,4). There is activation of stress adapting pathways which is thought to improve the somatic symptoms and psychic distress in anxiety (3,4). Venlafaxine, is a serotonin norepinephrine reuptake inhibitor (3,4). This can alleviate anxiety in patients with GAD with and without depression (3,4). Anxiety was illustrated to be reduced effectively at doses 75 to 225 mg/day in a 8 week trial (3,4). The response was maintained over additional 6 months of treatment (3,4). The adverse effect and safety profile is more favourable than the other TCAs (3,4). Common side effects include nausea, dry mouth, dizziness, sweating, constipation, sommonlence and anorexia (3,4). Venlafaxine is metabolism through the liver via CYP2D6 to the active metabolite: O desmethylvenlafaxine (3,4). It is excreted majorly (87%) through the urinary route (3,4).

Drug disease concerns

Venlafaxine may cause a sustained increase in blood pressure or tachycardia (1). Thus it is important for pre-existing hypertension to be controlled prior towards initiation of venlafaxine (1). This should also be cautioned in hepatic impairment as clearance is decreased and the plasma concentrations will be increased (1). Dose adjustment is recommended in mild to moderate hepatic impairment (1). In renal impairment, caution is advised as clearance is decreased and plasma concentrations will also be increased (1). Dose reduction is recommended in patients that have mild renal impairment (1).

Venlafaxine should not be used with agents that lower the seizure threshold, as concurrent therapy may lower the seizure even further (1). Venlafaxine should also be avoided in MAOI as the potential for serotonin syndrome is increased (1). Do not begin venlafaxine within 14 days of terminating MAO-I therapy and do not initiate MAOI treatment within 7 days of discontinuing venlafaxine (1). SSRIs such as paroxetine, escitalopram and sertraline are shown to be significantly more effective than placebo at reducing symptoms of anxiety (4). Paroxetine when taken at doses of 20 mg to 40 mg / day had a 62-68% response in patients over 8 weeks of treatment (4). There was remission in 30% to 60% of patients (4). Paroxetine was associated with high rates of somnolence, nausea, abnormal ejaculation, dry mouth, decreased libido, and asthenia compared to placebo however (4). Paroxetine is extensively metabolized via CYP2D6 enzymes (4). The primary metabolites are the oxidation and methylation of the parent drug, with subsequent sulfate/glucuronide conjugation (4). Paroxetine is a substrate of CYP2D6 and inhibits CYP1A2 (weak), CYB2B6 (moderate), CYP2C19 (weak), CYP2C9 (weak), CYP2D6 (strong) and CYP3A4 (weak) (4). Alcohol may enhance the toxic/adverse effects of paroxetine when taken together (4). The risk of psychomotor impairment may be enhanced (4). The serotonergic effects of antidepressants may be enhanced when taken together with paroxetine (4). The risk of serotonin syndrome is increased (4). This medication should be avoided in hepatic and renal impairment. Dosage adjustments may be needed (4).

BZDs when given at low doses can be used for several weeks at a time for symptomatic relief (1,4). It results in an improvement in 65-75% of GAD patients (1,4). Most of the improvement occurs during the first 2 weeks of therapy (1,4). These are more effective at treating somatic than psychiatric symptoms though (1,4). There is a lack of effectiveness in treating depression and there is a risk of dependency and abuse (1,4). The MOA of BZD is through the enhancement of the transmission of GABA through interaction with GABAa-receptor complex (1,4). All of the BZD are expected to have equal benefit in comparable doses (1,4). These are metabolized by hepatic oxidation via cytochrome P-450 3A4 and glucuronide conjugation (1,4). Lorazepam and oxazepam are differ as they bypass hepatic oxidation and are conjugated only (1,4). These are preferred in patients who have hepatic function (1,4). Common side effects include CNS depressive effects (drowsiness, sedation, psychomotor impairment) and cognitive effects such as poor recall memory (1,4). Upon discontinuation of the BZD, there is withdrawal, rebound anxiety and high rates of relapse (1,4). The severity of such effects is increased upon higher doses of BZDs and longer duration of therapies (1,4). Patients should be tapered rather than discontinued rapidly from BZDs to avoid these withdrawal symptoms (1,4). The duration of the taper is proportional with the duration of BZD therapy (1,4). The longer the duration of BZD therapy is, the longer the tapering period (1,4). A general approach is to reduce the dose by 25% every 5 to 7 days until half the original dose is reached then decrease by 10 to 12% per week until discontinued (1,4). Minor withdrawal symptoms and discomfort should be expected upon tapering (1,4). Rebound symptoms are transient in nature (1,4). This is not a relapse and patients should be counseled on this (1,4).


  1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 7th ed. Toronto: McGraw-Hill; 2007. p. 1161.
  2. Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT. Pharmacotherapy: Principles and Practice. McGraw-Hill: 2008. p. 610.
  3. Kroenke K, Spitzer RL, Williams JB, et al. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007; 146:317.
  4. Mahe V, Balogh A. Long-term pharmacological treatment of generalized anxiety disorder. Int Clin Psychopharmacol. 2000; 15:99.


This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers

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